Emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating bacterial infections. One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have reviewed novel approaches to developing new antibiotics. However, the development of new antibacterial agents is a challenging task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have reviewed the challenges in the discovery of antibacterial agents.
In general, majority of the antibacterial agents in use today belong to the beta-lactam class of antibacterial agents (such as, for example, penicillins, cephalosporins, carbapenems, monobactams etc.) owing to their established efficacy and safety. In addition, the beta-lactam class of antibacterial agents has consistently remained attractive due to their chemical maneuverability thereby generating clinically relevant agents with a diverse therapeutic profile. The beta-lactam class of antibacterial agents target several bacterial enzymes, collectively termed as penicillin binding proteins (PBPs) located on cytoplasmic membrane facing periplasmic space. PBPs are necessary for growth and maintenance of peptidoglycan layer, which forms part of the bacterial cell wall and protects the cell from osmotic stress. Inhibition of peptidoglycan biosynthesis therefore results in bacterial cell growth inhibition and/or killing. The ability of various beta-lactam compounds to act as antibacterial agents originates from their ability to bind with one or more PBPs and interfere with the bacterial cell wall synthesis. Thus, inhibition of essential high molecular weight PBPs such as PBPs 1a or 1b, 2 and 3 is critical for bacterial cell lysis. Agents that bind to more than one essential PBP with high affinities are significantly more cidal as compared to agents that bind to single PBPs.
Heavy use of antibacterial agents has resulted in bacteria developing resistance to known antibacterial agents through various mechanisms. For example, resistance in Staphylococci is mediated by synthesis of penicillinase and acquisition of modified PBP2a by the bacteria. Modifications in the target PBPs has also played an important role in the development of resistance to beta-lactam antibacterial agents. A more common mechanism by which bacteria acquire resistance to beta-lactam antibacterial agents is by producing beta-lactamase enzymes, which inactivate the beta-lactam antibacterial agents. To some extent, this problem was overcome by using various beta-lactamase inhibitors (for example, clavulanic acid, sulbactam etc.). However, this approach too has limitations. For example, clinically available effective inhibitors for carbapenem hydrolyzing oxacillinases and metallo beta-lactamase enzymes are not available. This means, treatment options for infections caused by pathogens expressing such extended spectrum beta-lactamases (ESBL) are limited to the agents such as colistin which is associated with severe adverse effects and inconsistent efficacy.
In view of this, there is an urgent need to resurrect otherwise well-established but now compromised beta-lactam antibacterial agents in a manner that could bypass the need for inhibiting diverse beta-lactamase enzymes and provide an effective approach for treating infections caused by strains expressing multiple mechanisms of beta-lactam resistance including suboptimal drug uptake. The inventors have now surprisingly discovered pharmaceutical compositions and methods for treating bacterial infections, including those caused by resistant bacteria. The composition and methods according to the invention use at least one antibacterial agent or a pharmaceutically acceptable derivative thereof, in combination with an enhancer compound or a pharmaceutically acceptable derivative thereof; wherein the enhancer compound is: (i) beta-lactamase stable, and (ii) a selective and high affinity PBP binder.